Piperdines for use as orexin receptor antagonists

ABSTRACT

Disclosed are compounds of formula (I):                    
     wherein: 
     Y represents a group (CH 2 ) n , wherein n represents 0, 1 or 2; 
     R 1  is phenyl, naphthyl, a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; or a group NR 3 R 4  wherein one of R 3  and R 4  is hydrogen or optionally substituted (C 1-4 )alkyl and the other is phenyl, naphthyl or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S, or R 3  and R 4  together with the N atom to which they are attached form a 5 to 7-membered cyclic amine which has an optionally fused phenyl ring; any of which R 1  groups may be optionally substituted; 
     R 2  represents phenyl or a 5- or 6-membered heteroaryl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is substituted by R 5 , and further optional substituents; or R 2  represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; 
     R 5  represents an optionally substituted (C 1-4 )alkoxy, halo, optionally substituted (C 1-6 )alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S; or pharmaceutically acceptable salts thereof.

This application ia a 371 of PCT/EP01/06752 filed Jun. 13, 2001, nowWO01/963202.

This invention relates to N-aroyl cyclic amine derivatives and their useas pharmaceuticals.

Many medically significant biological processes are mediated by proteinsparticipating in signal transduction pathways that involve G-proteinsand/or second messengers.

Polypeptides and polynucleotides encoding the human 7-transmembraneG-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have beenidentified and are disclosed in EP-A-875565, EP-A-875566 and WO96/34877. Polypeptides and polynucleotides encoding a second humanorexin receptor, orexin-2 (HFGANP), have been identified and aredisclosed in EP-A-893498.

Polypeptides and polynucleotides encoding polypeptides which are ligandsfor the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed inEP-A-849361.

Orexin receptors are found in the mammalian host and may be responsiblefor many biological functions, including pathologies including, but notlimited to, depression; anxiety; addictions; obsessive compulsivedisorder; affective neurosis/disorder, depressive neurosis/disorder;anxiety neurosis; dystymic disorder; behaviour disorder; mood disorder;sexual dysfunction; psychosexual dysfunction; sex disorder; sexualdisorder; schizophrenia; manic depression; delerium; dementia; severemental retardation and dyskinesias such as Huntington's disease andGilles de la Tourett's syndrome; disturbed biological and circadianrhythms; feeding disorders, such as anorexia, bulimia, cachexia, andobesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma;cancer; Parkinson's disease; Cushing's syndrome/disease; basophiladenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysistumor/adenoma; hypothalamic diseases; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;pituitary growth hormone; adrenohypophysis hypofunction;adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman'ssyndrome (anosmia, hyposmia); functional or psychogenic amenorrhea;hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenaldysfunction; idiopathic hyperprolactinemia; hypothalamic disorders ofgrowth hormone deficiency; idiopathic growth hormone deficiency;dwarfism; gigantism; acromegaly; disturbed biological and circadianrhythms; and sleep disturbances associated with such diseases asneurological disorders, neuropathic pain and restless leg syndrome,heart and lung diseases; acute and congestive heart failure;hypotension; hypertension; urinary retention; osteoporosis; anginapectoris; myocardial infarction; ischaemic or haemorrhagic stroke;subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhageassociated with traumatic head injury; ulcers; allergies; benignprostatic hypertrophy; chronic renal failure; renal disease; impairedglucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain, such as hyperalgesia, causalgia and allodynia;acute pain; burn pain; atypical facial pain; neuropathic pain; backpain; complex regional pain syndromes I and II; arthritic pain; sportsinjury pain; pain related to infection, e.g. HIV, post-polio syndrome,and post-herpetic neuralgia; phantom limb pain; labour pain; cancerpain; post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; conditions associated with visceral pain including irritablebowel syndrome, migraine and angina; urinary bladder incontinence e.g.urge incontinence; tolerance to narcotics or withdrawal from narcotics;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; and neurodegenerative disorders, which includes nosologicalentities such as disinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

Experiments have shown that central administration of the ligandorexin-A (described in more detail below) stimulated food intake infreely-feeding rats during a 4 hour time period. This increase wasapproximately four-fold over control rats receiving vehicle. These datasuggest that orexin-A may be an endogenous regulator of appetite.Therefore, antagonists of its receptor may be useful in the treatment ofobesity and diabetes, see Cell, 1998, 92, 573-585.

There is a significant incidence of obesity in westernised societiesAccording to WHO definitions a mean of 35% of subjects in 39 studieswere overweight and a further 22% clinically obese. It has beenestimated that 5.7% of all healthcare costs in the USA are a consequenceof obesity. About 85% of Type 2 diabetics are obese, and diet andexercise are of value in all diabetics. The incidence of diagnoseddiabetes in westernised countries is typically 5% and there areestimated to be an equal number undiagnosed. The incidence of bothdiseases is rising, demonstrating the inadequacy of current treatmentswhich may be either ineffective or have toxicity risks includingcardiovascular effects. Treatment of diabetes with sulfonylureas orinsulin can cause hypoglycaemia, whilst metformin causes GIside-effects. No drug treatment for Type 2 diabetes has been shown toreduce the long-term complications of the disease. Insulin sensitiserswill be useful for many diabetics, however they do not have ananti-obesity effect.

Rat sleep/EEG studies have also shown that central administration oforexin-A, an agonist of the orexin receptors, causes a dose-relatedincrease in arousal, largely at the expense of a reduction inparadoxical sleep and slow wave sleep 2, when administered at the onsetof the normal sleep period. Therefore antagonists of its receptor may beuseful in the treatment of sleep disorders including insomnia.

International Patent Applications WO99/09024, WO99/58533, WO00/47577 andWO00/47580 disclose phenyl urea derivatives and WO00/47576 disclosesquinolinyl cinnamide derivatives as orexin receptor antagonists.

The present invention provides N-aroyl cyclic amine derivatives whichare non-peptide antagonists of human orexin receptors, in particularorexin-1 receptors. In particular, these compounds are of potential usein the treatment of obesity, including obesity observed in Type 2(non-insulin-dependent) diabetes patients, and/or sleep disorders.

According to the invention there is provided a compound of formula (I):

wherein:

Y represents a group (CH₂)_(n), wherein n represents 0, 1 or 2;

R¹ is phenyl, naphthyl, a mono or bicyclic heteroaryl group containingup to 3 heteroatoms selected from N, O and S; or a group NR³R⁴ whereinone of R³ and R⁴ is hydrogen or optionally substituted (C₁₋₄)alkyl andthe other is phenyl, naphthyl or a mono or bicyclic heteroaryl groupcontaining up to 3 heteroatoms selected from N, O and S, or R³ and R⁴together with the N atom to which they are attached form a 5 to7-membered cyclic amine which has an optionally fused phenyl ring; anyof which R¹ groups may be optionally substituted;

R² represents phenyl or a 5- or 6-membered heteroaryl group containingup to 3 heteroatoms selected from N, O and S, wherein the phenyl orheteroaryl group is substituted by R⁵, and further optionalsubstituents; or R² represents an optionally substituted bicyclicaromatic or bicyclic heteroaromatic group containing up to 3 heteroatomsselected from N, O and S;

R⁵ represents an optionally substituted (C₁₋₄)alkoxy, halo, optionallysubstituted (C₁₋₆)alkyl, optionally substituted phenyl, or an optionallysubstituted 5- or 6-membered heterocyclic ring containing up to 3heteroatoms selected from N, O and S;

or a pharmaceutically acceptable salt thereof.

Y is preferably (CH₂)_(n) wherein n is 1.

A specific group of compounds which may be mentioned are those in whichR¹ is phenyl, naphthyl or a mono or bicyclic heteroaryl group containingup to 3 heteroatoms selected from N, O and S; any of which may beoptionally substituted. Preferably R¹ is an optionally substitutedphenyl or benzofuranyl. The phenyl group may have up to 5, preferably 1,2 or 3 optional substituents.

When R¹ is a group NR³R⁴ preferably one of R³ and R⁴ is optionallysubstituted phenyl. The phenyl group may have up to 5, preferably 1, 2or 3 optional substituents.

Examples of groups where R¹ or one of R³ and R⁴ is a mono or bicyclicheteroaryl group containing up to 3 heteroatoms selected from N, O andS, include pyridyl, furanyl, indolyl, benrzofuranyl, quinolinyl,isoquinolinyl, pyrazinyl, quinoxalinyl, benzoxazolyl, pyrazolyl,isoxazolyl, azaindolyl, indazolyl or naphthyridinyl. An alternativegroup is pyridyl, furayl, indolyl, benzofuranyl, quinolinyl,isoquinolinyl, pyrazinyl and quinoxalinyl. Most preferably R¹ isoptionally substituted phenyl or benzofuranyl.

When R³ and R⁴ together with the N atom to which they are attached forma 5 to 7-membered cyclic amine which has an optionally fused phenyl ringsaid group is preferably an indolinyl moiety optionally substituted byfluoro, chloro, cyano, methyl, trifluoromethyl, methoxy ortrifluoromethoxy.

Preferably where R² represents phenyl or a heteroaryl group the R⁵ groupis situated adjacent to the point of attachment to the amide carbonyl.

Examples of groups where R² represents a 5- or 6-membered heteroarylgroup containing up to 3 heteroatoms selected from N, O and S, includethiazolyl, pyrazolyl, triazolyl, pyridazyl isoxazolyl, and thiophenyl.

Preferably R² represents optionally substituted phenyl, thiazolyl,pyrazolyl, 1,2,3-triazolyl, pyridazyl, isoxazolyl, or thiophenyl. R² mayrepresent optionally substituted phenyl,thiazolyl, pyrazoly,1,2,3-triazolyl, pyridazyl or isoxazolyl.

Examples of groups where R⁵ is a 5- or 6-membered heterocyclyl groupcontaining up to 3 heteroatoms selected from N, O and S, includefuranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl,pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl orpyrimidinyl.

More preferably R⁵ may represent a trifluoromethoxy group, halo,(C₄₋₆)alkyl, optionally substituted phenyl or an optionally substituted5- or 6-membered heterocyclic ring containing up to 3 heteroatomselected from N, O, S.

Even more preferably R⁵ represents an optionally substitutedphenyl,pyridyl, oxadiazolyl, furanyl, pyrimidinyl or methoxy group.

Most preferably R⁵ is selected from trifluoromethoxy, methoxy, halo, oran optionally substituted phenyl, pyridyl, pyrazolyl or oxadiazolylgroup.

Optional substituents for the groups R¹ to R⁵ include halogen, hydroxy,oxo, cyano, nitro, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halo(C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, aryl(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl(C₁₋₄)alkoxy, (C₁₋₄)alkanoyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylsulfonyl, (C₁₋₄)alkylsulfonyloxym,(C₁₋₄)alkylsulfonyl(C₁₋₄)alkyl, arylsulfonyl, arylsulfonyloxy,arylsulfonyl(C₁₋₄)alkyl, (C₁₋₄)alkylsulfonamido, (C₁₋₄)alkylamido,(C₁₋₄)alkylsulfonamido(C₁₋₄)alkyl, (C₁₋₄)alkylamido(C₁₋₄)alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamido(C₁₋₄)alkyl,arylcarboxamido(C₁₋₄)alkyl, aroyl, aroyl(C₁₋₄)alkyl, oraryl(C₁₋₄)alkanoyl group; a group R^(a)R^(b)N—, R^(a)OCO(CH₂)_(r),R^(a)CON(R⁴)(CH₂)_(r), R^(a)R^(b)NCO(CH₂)_(r), R^(a)R^(b)NSO₂(CH₂)_(r)or R^(a)SO₂NR^(b)(CH₂)_(r) where each of R^(a) and R^(b) independentlyrepresents a hydrogen atom or a (C₁₋₄)alkyl group or where appropriateR^(a)R^(b) forms part of a (C₃₋₆)azacyloalkane or(C₃₋₆)(2-oxo)azacycloalkane ring and r represents zero or an integerfrom 1 to 4. Alternative substitiuents include hydroxy(C₁₋₄)alkyl, andhydroxy(C₂₋₄)alkoxy.

In addition R¹ may be optionally substituted by a phenyl ring optionallysubstituted by a halogen, cyano or (C₁₋₄)alkanoyl; or by a 5- or6-membered heterocyclic ring, optionally substituted by a (C₁₋₂)alkyl orR^(a)R^(b)N— group; wherein R^(a) and R^(b) are as defined above.

Preferred optional substituents for R² are halogen, cyano, optionallysubstituted (C₁₋₆)alkyl, optionally substituted (C₁₋₆)alkoxy, orR^(a)R^(b)N— wherein R^(a) and R^(b) independently represent a hydrogenatom or a (C₁₋₄)alkyl group.

In the groups R¹ to R⁵, substituents positioned ortho to one another maybe linked to form a ring.

When a halogen atom is present in the compound of formula (I) it may befluorine, chlorine, bromine or iodine.

When the compound of formula (I) contains an alkyl group, whether aloneor forming part of a larger group, e.g. alkoxy or allylthio, the alkylgroup may be straight chain, branched or cyclic, or combinationsthereof, it is preferably methyl or ethyl.

It will be appreciated that compounds of formula (I) may exist as R or Senantiomers. The present invention includes within its scope all suchisomers, including mixtures. Where additional chiral centres are presentin compounds of formula (I), the present invention includes within itsscope all possible diastereoismers, including mixtures thereof. Thedifferent isomeric forms may be separated or resolved one from the otherby conventional methods, or any given isomer may be obtained byconventional synthetic methods or by stereospecific or asymmetricsyntheses.

It will be understood that the invention includes pharmaceuticallyacceptable derivatives of compounds of formula (I) and that these areincluded in the scope of the invention.

As used herein “pharmaceutically acceptable derivative” includes anypharmaceutically acceptable salt or ester or salt of such ester of acompound of formula (I) or which upon administration to the recipient iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite thereof.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable salts.

It will be appreciated that for use in medicine the salts ofthecompounds of formula (I) should be pharmaceutically acceptable.Suitable pharmaceutically acceptable salts will be apparent to thoseskilled in the art and include acid addition salts formed with inorganicacids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoricacid; and organic acids e.g. succinic, maleic, acetic, fuimaric, citric,tartaric, benzoic, p-toluenesulfonic, methanesulfonic ornaphthalenesulfonic acid. Other salts e.g. oxalates, may be used, forexample in the isolation of compounds of formula (I) and are includedwithin the scope of this invention. Also included within the scope ofthe invention are solvates and hydrates of compounds of formula (I).

Certain of the compounds of formula (I) may form acid addition saltswith one ormore equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure forms for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

According to a further feature of the invention there is provided aprocess for the preparation of compounds of formula (I) and saltsthereof. The following schemes detail synthetic routes to compounds ofthe invention.

wherein Y and R² are as defined for formula (I), R¹ is phenyl, naphthyl,or a mono or bicyclic heteroaryl group containing up to 3 heteroatomsselected from N, O and S, which groups may be optionally substituted, Pis a protecting group and L¹ and L² are leaving groups.

Examples of protecting groups P include t-butyloxycarbonyl,trifluoroacetyl, benzyloxycarbonyl and optionally substituted benzyl.Deprotection conditions, step (ii), will depend on the particularprotecting group; for the groups mentioned above these are respectively,acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g.potassium carbonate in a solvent such as aqueous methanol) and catalytichydrogenolysis in an inert solvent (e.g. using palladium on charcoal ina lower alcohol or ethyl acetate).

Examples of suitable leaving groups L¹ and L² include halogen, hydroxy,OC(═O)alkyl OC(═O)O-alkyl and OSO₂Me. Steps (i) and (iii) may be carriedout using a wide range of known acylation conditions, e.g. in an inertsolvent such as dichloromethane, in the presence of a base such astriethylamine. Alternatively these steps may be carried out when L¹ orL² represents hydroxy, in which case the reaction takes place in aninert solvent such as dichloromethane in the presence of a diimidereagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, and an activator such as 1-hydroxybenzotriazole.

wherein Y, R², R³ and R⁴ are as defined for formula (I), P is aprotecting group as described for Scheme 1 and L² is a leaving group asdescribed for Scheme 1. Formation of the urea bond, step (iv), may becarried out using methods know to those skilled in the art. For example,in an inert solvent such as dichloromethane by use of a suitableisocyanate reagent, either directly or generated in situ from a suitableacid, or acid derivative, and an azide reagent such as diphenylphosphoryl azide. Step (iv) may also be achieved by reaction with acarbamoyl chloride reagent either directly, or generated in situ fromsuitable amines with reagents such as phosgene or triphosgene.Alternatively this reaction may be carried out with a suitable amine inan inert solvent in the presence of dicarbonyl reagents such as1,1′-dicarbonyldiimidazole. Step (vi) may be achieved using a wide rangeof acylation conditions as described for Scheme 1.

wherein Y, R¹, R², R³ and R⁴ are as defined for formula (I), P and P¹are amino protecting groups as described for Scheme 1 and L¹ and L² areleaving groups as described for Scheme 1.

Examples of protecting groups P and P¹ include t-butyloxycarbonyl,trifluoroacetyl, benzyloxycarbonyl and optionally substituted benzyl.Deprotection conditions, step (x), will depend on the particularprotecting group; for the groups mentioned above these are respectively,acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g.potassium carbonate in a solvent such as aqueous methanol) and catalytichydrogenolysis in an inert solvent (e.g. using palladium on charcoal ina lower alcohol or ethyl acetate). In scheme 3, protecting groups P andP¹ are selected to be different. Step (xii) can be carried out asdescribed for step (iv) in Scheme 2.

wherein Y and R² are as defined for formula (I), R¹ is phenyl, naphthyl,or a mono or bicyclic heteroaryl group containing up to 3 heteroatomsselected from N, O and S which groups may be optionally substituted andL¹ and L² are leaving groups as described for Scheme 1.

Compound (A) may be prepared as described in O. Froelich et al., Tet.Asym. 1993, 4 (11), 2335 and references therein.

wherein Y, R², R³ and R⁴ are as defined for formula (I), and L² is aleaving group as described for Scheme 1. Step (xix) can be carried outas described for step (iv) in Scheme 2.

The starting materials for use in Schemes 1 to 5 are commerciallyavailable, known in the literature or can be prepared by known methods.Within the schemes above there is scope for functional groupinterconversion.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, e.g. 5 to 1000, preferably 10 to 100compounds of formula (I). Compound libraries may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesisusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I), orpharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are useful for the treatment of diseases or disorders wherean antagonist of a human orexin receptor is required such as obesity anddiabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders ofgrowth hormone deficiency; idiopathic growth hormone deficiency;Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome;heart and lung diseases; depression; anxiety; addictions; obsessivecompulsive disorder; affective neurosis/disorder; depressiveneurosis/disorder; anxiety neurosis; dysthymic disorder; behaviourdisorder; mood disorder; sexual dysfunction; psychosexual dysfunction;sex disorder; sexual disorder; schizophrenia; manic depression;delerium; dementia; bulimia and hypopituitarism.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are particularly useful for the treatment of obesity,including obesity associated with Type 2 diabetes, and sleep disorders.

Other diseases or disorders which may be treated in accordance with theinvention include disturbed biological and circadian rhythms;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;adrenohypophysis hypofunction; functional or psychogenic amenorrhea;adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhancedor exaggerated sensitivity to pain such as hyperalgesia, causalgia andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndromes I and II; arthriticpain; sports injury pain; pain related to infection e.g. HIV, post-poliosyndrome and post-herpetic neuralgia; phantom limb pain; labour pain;cancer pain; post-chemotherapy pain; post-stroke pain; post-operativepain; neuralgia; and tolerance to narcotics or withdrawal fromnarcotics.

The invention also provides a method of treating or preventing diseasesor disorders where an antagonist of a human orexin receptor is required,which comprises administering to a subject in need thereof an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

The invention also provides a compound of formula (I), or apharmaceutically acceptable derivative thereof, for use in the treatmentor prophylaxis of diseases or disorders where an antagonist of a humanorexin receptor is required.

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for the treatment or prophylaxis of diseases or disorderswhere an antagonist of a human orexin receptor is required.

For use in therapy the compounds of the invention are usuallyadministered as a pharmaceutical composition. The invention alsoprovides a pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable carrier.

The compounds of formula (I) and their pharmaceutically acceptablederivatives may be administered by any convenient method, e.g. by oral,parenteral, buccal, sublingual, nasal, rectal or transdermaladministration, and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptablederivatives which are active when given orally can be formulated asliquids or solids, e.g. as syrups, suspensions, emulsions, tablets,capsules or lozenges.

A liquid formulation will generally consist of a suspension or solutionof the active ingredient in a suitable liquid carrier(s) e.g. an aqueoussolvent such as water, ethanol or glycerine, or a non-aqueous solvent,such as polyethylene glycol or an oil. The formulation may also containa suspending agent, preservative, flavouring and/or colouring agent.

A composition, in the form of a tablet can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidformulations, such as magnesium stearate, starch, lactose, sucrose andcellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, e.g. pellets containing the active ingredientcan be prepared using standard carriers and then filled into a hardgelatin capsule; alternatively a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), e.g. aqueousgums, celluloses, silicates or oils and the dispersion or suspensionthen filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe active ingredient in a sterile aqueous carrier or parenterallyacceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active ingredient in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea disposable dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve. Where the dosage formcomprises an aerosol dispenser, it will contain a propellant which canbe a compressed gas e.g. air, or an organic propellant such as afluorochloro-hydrocarbon or hydrofluorocarbon. Aerosol dosage forms canalso take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles where the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

The dose of the compound of formula (I), or a pharmaceuticallyacceptable derivative thereof, used in the treatment or prophylaxis ofthe abovementioned disorders or diseases will vary in the usual way withthe particular disorder or disease being treated, the weight of thesubject and other similar factors. However, as a general rule, suitableunit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unitdoses may be administered more than once a day for example two or threetimes a day, so that the total daily dosage is in the range of about0.01 to 100 mg/kg; and such therapy may extend for a number of weeks ormonths. In the case of pharmaceutically acceptable derivatives the abovefigures are calculated as the parent compound of formula (I).

No toxicological effects are indicated/expected when a compound offormula (I) is administered in the above mentioned dosage range.

Human orexin-A has the amino acid sequence:

pyroGlu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu1               5                10                  15 Tyr Glu Leu LeuHis Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr            20                25                 30 Leu-NH₂

Orexin-A can be employed in screening procedures for compounds whichinhibit the ligand's activation of the orexin-1 receptor.

In general, such screening procedures involve providing appropriatecells which express the orexin-1 receptor on their surface. Such cellsinclude cells from mammals, yeast, Drosophila or E. coli. In particular,a polynucleotide encoding the orexin-1 receptor is used to transfectcells to express the receptor. The expressed receptor is then contactedwith a test compound and an orexin-1 receptor ligand to observeinhibition of a functional response. One such screening procedureinvolves the use of melanophores which are transfected to express theorexin-1 receptor, as described in WO 92/01810.

Another screening procedure involves introducing RNA encoding theorexin-1 receptor into Xenopus oocytes to transiently express thereceptor. The receptor oocytes are then contacted with a receptor ligandand a test compound, followed by detection of inhibition of a signal inthe case of screening for compounds which are thought to inhibitactivation of the receptor by the ligand.

Another method involves screening for compounds which inhibit activationof the receptor by determining inhibition of binding of a labelledorexin-1 receptor ligand to cells which have the receptor on theirsurface. This method involves transfecting a eukaryotic cell with DNAencoding the orexin-1 receptor such that the cell expresses the receptoron its surface and contacting the cell or cell membrane preparation witha compound in the presence of a labelled form of an orexin-1 receptorligand. The ligand may contain a radioactive label. The amount oflabelled ligand bound to the receptors is measured, e.g. by measuringradioactivity.

Yet another screening technique involves the use of FILIPR equipment forhigh throughput screening of test compounds that inhibit mobilisation ofintracellular calcium ions, or other ions, by affecting the interactionof an orexin-1 receptor ligand with the orexin-1 receptor.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Examples illustrate the preparation of pharmacologicallyactive compounds of the invention. The Descriptions D1-D16 illustratethe preparation of intermediates to compounds of the invention.

In the Examples ¹H NMR's were measured at 250 MHz in CDCl₃ unlessotherwise stated.

Abbreviations used herein are as follows

MDC means methylenedichloride.

DMF means N,N-Dimethylformamide.

Description 1(a):(RS)-2-(Benzamidomethyl)-1-(t-butyloxycarbonyl)piperidine

Benzoyl chloride (1.64 g, 11.7 mmol) was added to a stirred mixture of(RS)2-(aminomethyl)-1-(t-butyloxycarbonyl)piperidine (2.50 g, 11.7 mmol)and triethylamine (2.4 ml, 17.6 mmol) in MDC (50 ml). The reactionmixture was stirred at 20° C. for 1 h under an atmosphere of argon, andthen washed with saturated aqueous sodium hydrogen carbonate (50 ml),then water (2×50 ml). The organic layer was dried (Na₂SO₄), filtered andevaporated in vacuo to give a yellow oil which was purified bychromatography on silica gel (100 g) eluting from 10-50% ethyl acetatein hexane to give the title compound as a yellow oil (3.37 g, 91%). ¹HNMR: 1.37 (9H, s), 1.67 (6H, m), 2.90 (1H, m), 3.28 (1H, m), 4.03 (2H,m), 4.56 (1H, m), 6.85 (1H, br s), 7.42 (3H, m), 7.78 (2H, m).

The following compound was prepared in a similar manner to Description1(a):

1(b): (RS)-1-(t-Butyloxycarbonyl)-2-(4-fluorobenzamidomethyl)piperidine

Mass Spectrum (API⁺): Found 337 (MH⁺). C₁₈H₂₅FN₂O₃ requires 336.

Description 2(a): (RS)-2-(Benzamidomethyl)piperidine

Trifluoroacetic acid (10 ml) was added to a solution of(RS)-2-(benzamidomethyl)-1-(t-butyloxycarbonyl)piperidine (3.36 g, 10.6mmol) in MDC (100 ml), and the mixture stirred at 20° C. under argon for1 h. The reaction mixture was evaporated in vacuo to give the titlecompound as a pale yellow oil (1.73 g, 75%). Mass Spectrum (API⁺): Found219 (MH⁺). C₁₃H₁₈N₂O requires 218. ¹H-NMR δ: 1.20 (1, m), 1.30-1.77 (5,m), 1.83 (1H, m), 2.64 (1H, m), 2.80 (1H, m), 3.08 (1H, m), 3.26 (1H,m), 3.52 (1H, m), 6.71 (1H, br s), 7.47 (3H, m), 7.79 (2H, m).

The following compound was prepared in a similar manner to Description2(a):

2(b): (RS)-2-(4-Fluorobenzamidomethyl)piperidine

Mass Spectrum (API⁺): Found 237 (MH⁺). C₁₃H₁₇FN₂O requires 236.

Description 3(a):(RS)-1-(1-Butyloxycarbonyl)-2-((3-phenylureido)methyl)piperidine

To a solution of (RS)-(2-aminomethyl)-1-(t-butyloxycarbonyl)piperidine(1 g, 5 mmol) in MDC (10 ml) at 0° C. under argon was addedphenylisocyanate (0.6 ml, 5.5 mmol) in MDC (2 ml) dropwise over 10 min.The resulting solution was allowed to reach ambient temperature, andafter stirring overnight was evaporated to a gum which was redissolvedin MDC and washed successively with 1M HCl, and brine, dried (Na₂SO₄)and evaporated. Chromatography of the residue on silica gel, elutingwith ethyl acetate-hexane mixtures, afforded the title product as acolourless solid (0.74 g, 45%). Mass Spectrum (API⁺): Found 334 (MH⁺).C₁₈H₂₇N₃O₃ requires 333. ¹1NMR δ: 1.40 (9H, s), 1.40-1.70 (6H, m), 2.91(1H, m), 3.00-3.30 (1H, br s), 3.60-3.85 (1H, br s), 3.93 (1H, m),4.254.40 (1H, m), 5.44 (1H, s), 6.90-7.10 (1H, m), 7.12 (1H, br s),7.20-7.50 (4H, m).

The following compound was prepared in a similar manner to Description3(a):

3(b):(RS)-1-(t-Butyloxycarbonyl)-2-((3-(4-fluoro)phenylureido)methyl)piperidine

Mass Spectrum (API⁺): Found 352 (MH⁺). C₁₈H₂₆FN₃O₃ requires 351.

Description 4(a): (RS)-2-((3-phenylureido)methyl)piperidine

A solution of(RS)-1-(t-butyloxycarbonyl)-2-((3-phenylureido)methyl)piperidine (0.73g, 2 mmol) in MDC (30 ml) and trifluoroacetic acid (5 ml) was stirred atambient temperature for 2 h and then evaporated. The resulting oil wasdissolved in 0.5M HCl (20 ml) and washed twice with ethyl acetate (20ml). The aqueous phase was basified to pH 14 with aqueous NaOH in thepresence of MDC (30 ml). The aqueous layer was separated and extractedwith MDC (4×50 ml). The combined organic extracts were dried (Na₂SO₄)and evaporated to a clear gum (0.37 g, 73%). Mass Spectrum (API⁺): Found234 (MH⁺). C₁₃H₁₉N₃O requires 233. ¹HNMR δ: 1.05-1.20 (1H, m), 1.20-1.45(2H, m), 1.50-1.70 (3H, m), 1.77 (1H, m), 2.50-2.75 (2H, m), 2.95-3.15(2H, m), 3.20-3.40 (1H, m), 5.77 (1H, m), 7.00-7.10 (1H, m), 7.20-7.35(4H, m), 7.73 (1H, br s).

The following compounds were prepared in a similar manner to Description4(a):

4(b): (RS)2-((3-(4-Fluoro)phenylureido)methyl)piperidine

Mass Spectrum (API⁺): Found 252 (MH⁺). C₁₃H₁₈FN₃O requires 251.

4(c): (RS)-2,3-Dihydroindole-1-carboxylic acid(Piperidine-2-ylmethyl)amide

Mass Spectrum (API⁺): Found 260 (MH⁺). C₁₅H₂₁N₃O requires 259.

Description 5:(RS)-1-(t-Butyloxycarbonyl)-2-(trifluoroacetamidomethyl)piperidine

Trifluoroacetic anhydride (1.03 ml, 7.3 mmol) was added dropwise to astirred solution of (RS)2-(aminomethyl)-1-(t-butyloxycarbonyl)piperidine(1.42 g, 6.63 mmol) and triethylamine (1.1 ml, 7.9 mmol) in anhydrousMDC at 0° C. under argon. The resultant mixture was stirred at 0° C. for2 h, then at ambient temperature for a further 66 h. The mixture waswashed with saturated aqueous sodium hydrogen carbonate (100 ml), dried(Na₂SO₄) and evaporated in vacuo to afford the title compound as acolourless solid (2.03 g, 99%). ¹H NMR δ: 1.20-1.60 (2H, m), 1.39 (9H,s), 1.60-1.80 (4H, m), 2.75-2.95 (1H, m), 3.10-3.30 (1H, m), 3.80-4.05(2H, m), 4.40-4.50 (1H, m), 7.10-7.70 (1H, br m).

Description 6: (RS)-2-(Trifluoroacetamidomethyl)piperidine

The title compound was prepared, in an identical manner to that outlinedin Description 2, from(RS)-1-(t-butyloxycarbonyl)-2-(trifluoroacetamidomethyl)piperidine (2 g,6.45 mmol) as a colourless solid (1.2 g, 89%). Mass Spectrum (API⁺):Found 211 (MH⁺). C₈H₁₃F₃N₂O requires 210.

Description 7(a):(RS)-1-((4-(2-Methyl-5-phenyl)thiazolyl)carbonyl)-2-(trifluoroacetamidomethyl)piperidine

The title compound was prepared, using the method of Description 1, from(RS)-2-(trifluoroacetamidomethyl)piperidine (0.6 g, 2.86 mmol) and2-methyl-5-phenylthiazole-4-carbonyl chloride (0.8 g, 3.37 mmol) as apale orange gum (1.1 g, 94%). Mass Spectrum (API⁺): Found 412 (MH⁺).C₁₉H₂₀F₃N₃O₂S requires 411.

The following compound was prepared in a similar manner to Description7(a):

7(b):(RS)-1-((2-(5-(3-Methyl)-1,2,4-oxadiazolyl))benzoyl)-2-(trifluoroacetamidomethyl)piperidine

Mass Spectrum (API⁺): Found 397 (MH⁺). C₁₈H₁₉F₃N₄O₃ requires 396.

7(c):(S)-2-(t-Butyloxyearbonylaminomethyl)-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Description 1, from(S)-2-(t-butyloxycarbonylaminomethyl)piperidine (0.9 g, 4.23 mmol) and2-methyl-5-(4-fluorophenyl)thiazole-4-carbonyl chloride (1.08 g, 4.23mmol) as a pale orange amorphous solid (1.6 g, 87%). Mass spectrum(API⁺): Found 434 (MH⁺). C₂₂H₂₈FN₃O₃S requires 433.

Description 8(a):(RS)-2-(Aminomethyl)-1-((4-(2-methyl-5phenyl)thiazolyl)carbonyl)piperidine

(RS)-1-((4-(2-Methyl-5-phenyl)thiazolyl)carbonyl)-2-trifluoroacetamidomethyl)piperidine(1.05 g, 2.55 mmol) and potassium carbonate (2.3 g, 16.6 mmol) inmethanol (50 ml) and water (10 ml) were heated at 83° C. for 1.5 h. Theresultant mixture was cooled, evaporated in vacuo and partitionedbetween MDC (100 ml) and 1M NaOH (100 ml). The aqueous layer wasextracted with MDC (2×100 ml) and the combined organics dried (Na₂SO₄)and evaporated in vacuo to yield the title compound as a colourless gum(0.64 g, 80%). Mass Spectrum (API⁺): Found 316 (MH⁺). C17H₂₁N₃OSrequires 315.

The following compound was prepared in a similar manner to Description8(a):

8(b):(RS)-2-(Aminomethyl)-1-((2-(5-(3-methyl)-1,2,4-oxadiazolyl))benzoylpiperidine

Mass Spectrum (API⁺): Found 301 (MH⁺). C₁₆H₂₀N₄O₂ requires 300.

Description 9(a):(R)-2-((S)-2-(4-Fluorobenzamidomethyl)piperidin-1-yl)-2-phenylethanol

A solution of 4-fluorobenzoyl chloride (0.46 ml, 3.89 mmol) in MDC (5ml) was added dropwise, with ice cooling, to a stirred solution of(R)-2-((S)-2-(aminomethyl)piperidin-1-yl)-2-phenylethanol (1.1 g, 3.89mmol) (O. Froelich et al. Tetrahedron Asymmetry. 1993, 4(11), 2335) andtriethylamine (1.62 ml, 11.66 mmol) in MDC (25 ml). The resultingsolution was allowed to stand at room temperature overnight, washed withsaturated aqueous sodium hydrogen carbonate (100 ml), dried (Na₂SO₄) andevaporated in vacuo. The residue was chromatographed on silica gel using30-100% ethyl acetate in hexane gradient elution to afford the titlecompound as a colourless solid (1.24 g, 74%). Mass Spectrum (API⁺):Found 357 (MH⁺). C₂₁H₂₅FN₂O₂ requires 356. [α]²⁵ _(D)=−74.2° (c=1,CHCl₃).

The following compound was prepared in a similar manner to Description9(a):

Description 9(b):(S)-2-((R)-2-(4-Fuorobenzamidomethyl)piperidin-1-yl)-2-phenylethanol

Mass Spectrum (API⁺): Found 357 (MH⁺). C₂₁H₂₅FN₂O₂ requires 356. [α]²⁴_(D)=+75.4° (c=1, CHCl₃).

Description 10(a): (S)-2-(4-Fluorobenzamidomethyl)piperidine

Palladium black (0.2 g) was added to a stirred solution of(R)-2-((S)-2-(4-fluorobenzamidomethyl)piperidin-1-yl)-2-phenylethanol(1.1 g, 3.09 mmol) in methanol (30 ml) under argon. To this mixture wasadded formic acid (11 drops, excess) and the resultant mixture stirredat room temperature for 1 h, filtered through a short pad of Kieselguhrand the filtrate evaporated in vacuo. The residue was partitionedbetween 1M HCl (10 ml), and ethyl acetate (50 ml). The aqueous layer wasbasified with 1M NaOH and extracted into MDC (3×50 ml). The combinedorganics were dried (Na₂SO₄) and evaporated in vacuo to afford the titlecompound as a colourless solid (0.72 g, 99%). Mass Spectrum (API⁺):Found 237 (MH⁺). C₁₃H₁₇FN₂O requires 236. [α]²⁵ _(D)=+21.2° (c=1, CHCl₃)

The following compound was prepared in a similar manner to Description10(a):

10(b): (R)-2-(4-Fluorobenzamidomethyl)piperidine

Mass Spectrum (API⁺): Found 237 (MH⁺). C₁₃H₁₇FN₂O requires 236. [α]²⁴_(D)=−23.7° (c=1, CHCl₃)

Description 11:(R)-2-((S2-((3-(4-Fluoro)phenylureido)methyl)piperidin-1-yl)-2-phenylethanol

A solution of 4-fluorophenyl isocyanate (0.44 ml, 3.89 mmol) in MDC (5ml) was added dropwise, with ice cooling, to a stirred solution of(R)-2-((S2-(aminomethyl)piperidin-1-yl)-2-phenylethanol (1.1 g, 3.89mmol) in MDC (25 ml). The resulting solution was allowed to stand atroom temperature overnight, evaporated in vacuo and the residuechromatographed on silica gel using 25-100% ethyl acetate in hexane,then 2-5% methanol in ethyl acetate gradient elution to yield the titlecompound as a colourless solid (1.16 g, 67%). Mass Spectrum (API⁺):Found 372. (MH⁺). C₂₁H₂₆FN₃O₂ requires 371. [α]²⁶ _(D)=−85.8° (c=1,CHCl₃).

Description 12: (S)-((3-(4-Fluoro)phenylureido)methyl)piperidine

The title compound was prepared, using the method of Description 10,from(R)-2-((S)2-((3-(4-fluoro)phenylureido)methyl)piperidin-1-yl)-2-phenylethanol(0.9 g, 2.43 mmol), as a colourless solid (0.53 g, 87%). Mass Spectrum(API⁺): Found 252 (MH⁺). C₁₃H₁₈FN₃O requires 251. [α]²⁵ _(D)=+48.8°(c=1, CHCl₃).

Description 13: (RS)-2,3-Dihydroindole-1-carboxylic Acid(Piperidine-(1-t-butyloxycarbonyl)-2-ylmethyl)amide

A solution of (RS)-2-(aminomethyl)-1-(t-butyloxycarbonyl)piperidine(2.14 g, 10 mmol) in anhydrous MDC (10 ml) was added dropwise to astirred solution of 1,1-carbonyldiimidazole (1.62 g, 10 mmol) inanhydrous MDC (25 ml) at room temperature under argon. The resultantmixture was stirred at room temperature for 1.5 h, evaporated in vacuoand the residue dissolved in anhydrous DMF (15 ml). To this solutionunder argon was added a solution of indoline (1.19 g, 10 mmol) inanhydrous DMF (5 ml) with stirring. The resulting mixture was heated at100° C. for 5 h, cooled and poured into water (500 ml). The mixture wasextracted with diethyl ether (2×250 ml) and the combined extracts dried(Na₂SO₄) and evaporated in vacuo. The residue was chromatographed on.silica gel using 10-50% ethyl acetate in hexane gradient elution toafford the title compound as a pale pink solid (3 g, 84%). Mass Spectrum(API⁺): Found 360 (MH⁺). C₂₀H₂₉N₃O₃ requires 359.

Description 14:(R)-2-((S)-2(t-Butyloxycarbonylaminomethyl)piperidin-1-yl)-2-phenylethanol

A solution of di-t-butyl dicarbonate (5.6 g, 25.6 mmol) in MDC (20 ml)was added dropwise, with ice cooling, to a stirred solution of(R)-2-((S-2-(aminomethyl)piperidin-1-yl)-2-phenylethanol (6 g, 25.6mmol) in MDC (180 ml). The resultant solution was stirred at roomtemperature for 16 h. Evaporation in vacuo afforded the title compoundas a thick gum (8.6 g, 100%). Mass Spectrum (API⁺): Found 335 (MH⁺).C₁₉H₃₀N₂O₃ requires 334.

Description 15: (S)-2-(t-Butyloxycarbonylaminomethyl)piperidine

A solution of(R)-2-((S)-2-(t-butyloxycarbonylaminomethyl)piperidin-1-yl)-2-phenylethanol(8 g, 23.96 mmol) in ethanol (150 ml) was hydrogenated at roomtemperature and atmospheric pressure in the presence of 10% palladium oncarbon paste containing 60% water (2.4 g) for. 18 h. Filtration throughKieselguhr and evaporation in vacuo gave a residue which was partitionedbetween saturated aqueous citric acid and ethyl acetate (200 ml ofeach). The organic layer was extracted with saturated citric acid (50ml) and the combined aqueous layers washed with ethyl acetate (100 ml),basified with 2N NaOH and extracted with MDC (3×100 ml). The combinedorganic extracts were dried (Na₂SO₄) and evaporated mi vacuo to give thetitle compound as a colourless solid (4.5 g, 87%). Mass Spectrum (API⁺):Found 215 (MH⁺). C₁₁H₂₂N₂O₂ requires 214.

Description 16:(S)-2-Aminomethyl-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)-carbonyl)piperidine

The title compound was prepared, using the method of Description 2(a),from(S)-2-(t-butyloxycarbonylaminomethyl)-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine(1.6 g, 3.7 mmol) as a pale brown gum (1.05 g, 85%). Mass Spectrum(API⁺): Found 334 (MH⁺). C₁₇H₂₀FN₃OS requires 333.

EXAMPLE 1

(RS)-2-(Benzamidomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl-piperdine

2-Methyl-5-phenylthiazole-4-carbonyl chloride (14.25 mg, 0.06 mmol) inMDC (1 ml) was added to a solution of (RS)-2-(benzamidomethyl)piperidine(10.9 mg, 0.05 mmol), and triethylamine (0.15 ml, 0.1 mmol) in MDC (2ml), and the mixture shaken at 20° C. for 0.5 h. The reaction mixturewas washed with saturated aqueous sodium hydrogen carbonate (3 ml). Theorganic layer was added directly onto a dry 10 g pre-packed silicacartridge and eluted with 30-100% ethyl acetate in hexane to give thetitle compound as a colourless oil (16.0 mg, 76%). Mass Spectrum (API):Found 420 (MH⁺). C₂₄H₂₅N₃O₂S requires 419. ¹H NMR δ: 1.29-1.83 (6H, m),2.47 and 2.69 (3H, 2×s) 2.70-3.06 (1H, m), 3.18 and 3.48 (1H, 2×m), 3.40and 4.68 (1H, 2×), 3.90—4.28 (1H, m), 4.03 and 5.09 (1H, 2×m), 7.19 (1H,m), 7.44 (7H, m), 7.84 and 8.03 (2H, 2×m), 8.21 (1H, br s).

The compounds of the Examples below were prepared from the appropriateamine and acid chloride using a similar procedure to that described inExample 1.

Example R² R¹ Mass Spectrum (Electrospray LC/MS) 2

—Ph Found MH⁺ 399. C₂₆H₂₆N₂O₂ requires 398 3

Found MH⁺ 417. C₂₆H₂₅FN₂O₂ requires 416 4

Found MH⁺ 438. C₂₄H₂₄FN₃O₂S requires 437 5

Found MH⁺ 435. C₂₆H₂₄F₂N₂O₂ requires 434 6

Found MH⁺ 456. C₂₄H₂₃F₂N₃O₂S requires 455 7

Found MH⁺ 435. C₂₆H₂₄F₂N₂O₂ requires 434 8

Found MH⁺ 453. C₂₆H₂₃F₃N₂O₂ requires 452

EXAMPLE 9

(RS)-1-((4-(2-Methyl-5-phenyl)thiazolyl)carbonyl)-2-((3-phenylureido)methyl)piperidine

2-Methyl-5-phenylthiazole-4-carbonyl chloride (35 mg, 0.15 mmol) in MDC(3 ml) was added to a solution of(RS)-2-((3-phenylureido)methyl)piperidine (35 mg, 0.15 mmol) andtriethylamine (45 mg, 0.45 mmol) in MDC (3 ml) and the mixture shaken atambient temperature overnight. The reaction mixture was washed withsaturated aqueous sodium hydrogen carbonate (4 ml). The organic layerwas added directly to a dry 10 g pre-packed silica cartridge and elutedwith 30-100% ethyl acetate-hexane mixtures to give the title compound asa pale orange oil (44 mg, 68%). Mass Spectrum (Electrospray LC/MS):Found 435 (MH⁺). C₂₄H₂₆N₄O₂S requires 434.

The compounds of the Examples below were prepared from the appropriateamine and acid chloride using a similar procedure to that described inExample 9.

Example R² R¹ Mass Spectrum (Electrospray LC/MS) 10

—NHPh Found MH⁺ 414. C₂₆H₂₇N₃O₂ requires 413 11

—NHPh Found MH⁺ 415. C₂₅H₂₆N₄O₂ requires 414 12

—NHPh(4-F) Found MH⁺ 471. C₂₄H₂₄F₂N₄O₂S requires 470 13

—NHPh(4-F) Found MH⁺ 450. C₂₆H₂₅F₂N₃O₂ requires 449

EXAMPLE 14

(RS)-2-((2-Furyl)carbonylaminomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Example 1, from(RS)-2-(aminomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine(0.03 g, 0.095 mmol) and 2-furoyl chloride (0.011 ml, 0.11 mmol) as acolourless solid (0.0245 g, 63%). Mass Spectrum (API⁺): Found 410 (MH⁺).C₂₂H₂₃N₃O₃S requires 409.

EXAMPLE 15

(RS)-2-(2-Pyridylamidomethyl)-1-((4(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine

A mixture of(RS)-2-(aminomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine(0.03 g, 0.095 mmol), pyridine-2-carboxylic acid (0.013 g, 0.105 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.02 g,0.105 mmol) and 1-hydroxybenzotriazole hydrate (0.005 g, 0.03 mmol) inMDC (3 ml) was shaken for 20 h. The resultant mixture was washed withsaturated aqueous sodium hydrogen carbonate (8 ml) and the organic layeradded directly onto a dry 10 g prepacked silica gel cartridge. Elutionwith 10-100% ethyl acetate in hexane gradient afforded the titlecompound as a colourless solid (0.031 g, 78%). Mass Spectrum (API⁺):Found 421 (MH⁺). C₂₃H₂₄N₄ O₂S requires 420.

The compounds of the Examples below were prepared from the appropriateamine and acid using similar procedures to that described in Examples 14and 15.

Example R² R¹ Mass Spectrum (Electrospray LC/MS) 16

Found MH⁺ 470. C₂₈H₂₇N₃O₂S requires 469 17

Found MH⁺ 438. C₂₄H₂₄FN₃O₂S requires 437 18

Found MH⁺ 438. C₂₄H₂₄FN₃O₂S requires 437 19

Found MH⁺ 445. C₂₅H₂₄N₄O₂S requires 444 20

Found MH⁺ 471. C₂₇H₂₆N₄O₂S requires 470 21

Found MH⁺ 456. C₂₆H₂₅N₅O₃ requires 455 22

Found MH⁺ 455. C₂₇H₂₆N₄O₃ requires 454

EXAMPLE 23

(RS)-2-((3-((4-Fluoro)phenyl)ureido)methyl)-1-((4-(2-methyl-5-phenyl)yl)carbonyl)piperidine

4-Florophenyl isocyanate (0.013 ml, 0.11 mmol) was added to a solutionof (RS)-2-(aminomethyl)-methyl-5-phenyl)thiazolyl)carbonyl)piperidine(0.03 g, 0.095 mmol) in MDC (2 ml), and the resultant solution allowedto stand at room temperature for 16 h. The solution was added to the topof a pre-packed 10 g silica gel cartridge and eluted with 30-100% ethylacetate in hexane gradient to afford the title compound as a colourlesssolid (0.023 g, 53%). Mass Spectrum (API): Found 453 (MH⁺). C₂₄H₂₅FN₄O₂S requires 452.

EXAMPLE 24

(RS)-2,3-Dihydroindole-1-carboxylic acid(1-(1-(2-(3-methyl-(1,2,4)-oxadiazol-5-yl)-phenyl)-methanoyl)piperidin-2-ylmethyl)amide

2-(3-Methyl-1,2,4-oxadiazol-5-yl)-benzoyl chloride (0.045 g, 0.2 mmol)in MDC (2.7 ml) was added to a solution of2,3-dihydroindole-1-carboxylic acid (piperidin-2-ylmethyl) amide (0.05g, 0.193 mmol) and triethylamine (0.1 ml, 0.72 mmol) in MDC (3 ml).After 20 h the reaction mixture was washed with saturated aqueous sodiumhydrogen carbonate (8 ml). The organic layer was added directly onto adry 10 g pre-packed silica gel cartridge and eluted with 10-100% ethylacetate in hexane gradient to afford the title compound as a colourlesssolid (0.043 g, 50%). Mass Spectrum (API⁺): Found 446 (MH⁺). C₂₅H₂₇N₅O₃requires 445.

The compounds of the Examples below were prepared from the appropriateamine and acid using a similar procedure to that described in Examples23 and 24.

Example R² R¹ Mass Spectrum (Electrospray LC/MS) 25

Found MH⁺ 461. C₂₆H₂₈N₄O₂S requires 460 26

Found MH⁺ 479. C₂₆H₂₇FN₄O₂S requires 478 27

Found MH⁺ 464. C₂₅H₂₆FN₅O₃ requires 463 28

Found MH⁺ 464. C₂₅H₂₆FN₅O₃ requires 463

EXAMPLE 29

(S)-2-(((4-Fluoro)phenyl)carbonylaminomethyl)-1-((4-(2-methyl-5phenyl)thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Example 1, from(S)2-(4-fluorobenzanidomethyl)piperidine (0.1 g, 0.42 mmol) and2-methyl-5-phenyl thiazole-4-carbonyl chloride (0.12 g, 0.51 mmol) as acolourless solid (0.16 g, 87%). Mass Spectrum (API⁺): Found 438 (MH⁺).C₂₄H₂₄FN₃ O₂S requires 437. [α]²⁶ _(D)=−132° (c=1, CHCl₃).

The compounds of the Examples below were prepared from the appropriateamine and acid chloride using a similar procedure to that described inExample 29.

Mass Spectrum (Electrospray Example R² R¹ * LC/MS) 30

S Found MH⁺ 417. C₂₆H₂₅FN₂O₂ requires 416 31

R Found MH⁺ 417. C₂₆H₂₅FN₂O₂ requires 416

EXAMPLE 32

(S)-2-((3-((4-Fluoro)phenyl)ureido)methyl)-1-((4-(2-methyl-5phenyl)thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Example 1, from(S)-2-((3-(4-fluoro)phenylureido)methyl)piperidine (0.1 g, 0.4 mmol) and2-methyl-5-phenyl thiazole-4-carbonyl chloride (0.12 g, 0.51 mmol) as acolourless solid (0.089 g, 57%). Mass Spectrum (API⁺): Found 453 (MH⁺).C₂₄H₂₅FN₄O₂S requires 452. [α]²³ _(D)=−63° (c−1, CHCl₃).

The compound of the Example below was prepared from the appropriateamine and acid chloride using a similar procedure to that described inExample 32.

Ex- Mass Spectrum am (Electrospray ple R² R¹ * LC/MS) 33

S Found MH⁺ 432. C₂₆H₂₆FN₃O₂ requires 431

EXAMPLE 34

(S)-2-((7-Benzofuranyl)carbonylaminomethyl)-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Example 15, from(S)-2-aminomethyl-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine(0.1 g, 0.3 mmol) and benzofuran-7-carboxylic acid (0.058 g, 0.36 mmol)as a colourless amorphous solid (0.102 g, 71%). Mass Spectrum(Electrospray LC/MS): Found 478 (MH⁺). C₂₆H₂₄FN₃O₃S requires 477.

The compounds of the Examples below were prepared using similar methodsto those previously described.

Example R² R¹ Mass Spectrum (Electrospray LC/MS)  35

Found MH⁺ 421. C₂₄H₂₅FN₄O₂ requires 420  36

Found MH⁺ 419. C₂₄H₂₃FN₄O₂ requires 418  37

Found MH⁺ 407. C₂₄H₂₃FN₂O₃ requires 406  38

Found MH⁺ 442. C₂₇H₂₄FN₃O₂ requires 441  39

Found MH⁺ 407. C₂₄H₂₃FN₂O₃ requires 406  40

Found MH⁺ 459. C₂₆H₂₆N₄O₂S requires 458  41

Found MH⁺ 459. C₂₆H₂₆N₄O₂S requires 458  42

Found MH⁺ 460. C₂₆H₂₅N₃O₃S requires 459  43

Found MH⁺ 460. C₂₆H₂₅N₃O₃S requires 459  44

Found MH⁺ 410. C₂₂H₂₃N₃O₃S requires 409  45

Found MH⁺ 471. C₂₇H₂₆N₄O₂S requires 470  46

Found MH⁺ 485. C₂₈H₂₈N₄O₂S requires 484  47

Found MH⁺ 471. C₂₇H₂₆N₄O₂S requires 470  48

Found MH⁺ 460. C₂₅H₂₅N₅O₂S requires 459  49

Found MH⁺ 422. C₂₂H₂₃N₅O₂S requires 421  50

Found MH⁺ 436. C₂₃H₂₅N₅O₂S requires 435  51

Found MH⁺ 460. C₂₅H₂₅N₅O₂S requires 459  52

Found MH⁺ 410. C₂₂H₂₃N₃O₃S requires 409  53

Found MH⁺ 470. C₂₈H₂₇N₃O₂S requires 469  54

Found MH⁺ 450. C₂₅H₂₇N₃O₃S requires 449  55

Found MH⁺ 471. C₂₇H₂₆N₄O₂S requires 470  56

Found MH⁺ 478. C₂₆H₂₇N₃O₄S requires 477  57

Found MH⁺ 464. C₂₅H₂₅N₃O₄S requires 463  58

Found MH⁺ 475. C₂₆H₂₆N₄O₃S requires 474  59

Found MH⁺ 460. C₂₆H₂₅N₃O₃S requires 459  60

Found MH⁺ 460. C₂₆H₂₅N₃O₃S requires 459  61

Found MH⁺ 456. C₂₄H₂₃F₂N₃O₂S requires 455  62

Found MH⁺ 468. C₂₅H₂₆FN₃O₃S requires 469  63

Found MNa⁺ 511. C₂₇H₂₅FN₄O₂S requires 488  64

Found MH⁺ 470. C₂₇H₂₆N₄O₂S requires 469  65

Found MH⁺ 471. C₂₆H₂₅N₅O₂S requires 470  66

Found MH⁺ 477. C₂₆H₂₅FN₄O₂S requires 476  67

Found MH⁺ 536. C₂₅H₂₄ ³⁵Cl₂FN₃O₃S requires 535  68

Found MH⁺ 507. C₂₇H₂₄F₂N₄O₂S requires 506  69

Found MH⁺ 440. C₂₂H₂₂FN₅O₂S requires 439  70

Found MH⁺ 459. C₂₆H₂₃FN₄O₃ requires 458  71

Found MH⁺ 517. C₂₅H₂₃ ³⁵Cl₂FN₄O₃ requires 516  72

Found MH⁺ 439. C₂₄H₂₄F₂N₄O₂ requires 438  73

Found MH⁺ 422. C₂₃H₂₄FN₅O₂ requires 421  74

Found MH⁺ 472. C₂₆H₂₅N₅O₂S requires 471  75

Found MH⁺ 440. C₂₂H₂₂FN₅O₂S requires 439  76

Found MNa⁺ 476. C₂₃H₂₄FN₅O₂S requires 453  77

Found MH⁺ 439. C₂₄H₂₄F₂N₄O₂ requires 438  78

Found MNa⁺ 496. C₂₄H₂₂F₃N₃O₂S requires 473  79

Found MNa⁺ 500. C₂₆H₂₄FN₃O₃S requires 477  80

Found MH⁺ 536. C₂₅H₂₄ ³⁵Cl₂FN₃O₃S requires 535  81

Found MH⁺ 496. C₂₆H₂₃F₂N₃O₃S requires 495  82

Found MH⁺ 461. C₂₆H₂₅FN₄O₃ requires 460  83

Found MH⁺ 496. C₂₆H₂₃F₂N₃O₃S requires 495  84

Found MH⁺ 474. C₂₄H₂₂F₃N₃O₂S requires 473  85

Found MH⁺ 456. C₂₄H₂₆FN₃O₃S requires 455  86

Found MH⁺ 442. C₂₃H₂₄FN₃O₃S requires 441  87

Found MH⁺ 453. C₂₄H₂₅FN₄O₂S requires 452  88

Found MH⁺ 439. C₂₄H₂₇FN₄O₃ requires 438  89

Found MH⁺ 440. C₂₃H₂₃F₂N₅O₂ requires 439  90

Found MH⁺ 424. C₂₃H₂₂FN₃O₂S requires 423  91

Found MNa⁺ 478. C₂₃H₂₆FN₅O₂S requires 455  92

Found MH⁺ 411. C₂₂H₂₃FN₄O₃ requires 410  93

Found MH⁺ 457. C₂₄H₂₃F₃N₄O₂ requires 456  94

Found MH⁺ 461. C₂₆H₂₅FN₄O₃ requires 460  95

Found MH⁺ 458. C₂₃H₂₂F₃N₅O₂ requires 457  96

Found MH⁺ 462. C₂₅H₂₄FN₅O₃ requires 461  97

Found MH⁺ 462. C₂₅H₂₄FN₅O₃ requires 461  98

Found MH⁺ 458. C₂₃H₂₂F₃N₅O₂ requires 457  99

Found MH⁺ 458. C₂₃H₂₂F₃N₅O₂ requires 457 100

Found MH⁺ 457. C₂₄H₂₃F₃N₄O₂ requires 456 101

Found MH⁺ 461. C₂₆H₂₅FN₄O₃ requires 460 102

Found MH⁺ 443. C₂₃H₂₁F₃N₄O₂ requires 442 103

Found MH⁺ 447. C₂₅H₂₃FN₄O₃ requires 446 104

Found MH⁺ 553. C₂₈H₂₆ ³⁵ClFN₄O₃S requires 552 105

Found MH⁺ 456. C₂₄H₂₃ ³⁵ClFN₃O₃ requires 455 106

Found MH⁺ 461. C₂₅H₂₄N₄O₃S requires 460. 107

Found MH⁺ 457. C₂₃H₂₂F₂N₄O₂S requires 456. 108

Found MNa⁺ 496. C₂₄H₂₂F₃N₃O₂S requires 473 109

Found MH⁺ 457. C₂₄H₂₃F₃N₄O₂ requires 456 110

Found MH⁺ 456. C₂₄H₂₃F₂N₃O₂S requires 455 111

Found MH⁺ 474. C₂₄H₂₂F₃N₃O₂S requires 473 112

Found MH⁺ 474. C₂₄H₂₂F₃N₃O₂S requires 473 113

Found MH⁺ 456. C₂₄H₂₃F₂N₃O₂S requires 455 114

Found MH⁺ 456. C₂₄H₂₃F₂N₃O₂S requires 455 115

Found MH⁺ 503. C₂₇H₂₃FN₄O₃S requires 502 116

Found MH⁺ 441. C₂₃H₂₅FN₄O₂S requires 440 117

Found MH⁺ 457. C₂₃H₂₂F₂N₄O₂S requires 456 118

Found MNa⁺ 465. C₂₂H₂₀F₂N₄O₂S requires 442 119

Found MNa⁺ 505. C₂₄H₂₀F₂N₄O₃S requires 482 120

Found MH⁺ 443. C₂₂H₂₀F₂N₄O₂S requires 442 121

Found MH⁺ 503. C₂₅H₂₅F₃N₄O₂S requires 502 122

Found MH⁺ 507. C₂₇H₂₇FN₄O₃S requires 506

EXAMPLE 123

(S)-2-((4-Benzofuranyl)carbonylaminomethyl)-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Example 1, from(S)-2-aminomethyl-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine(0.1 g, 0.3 mmol) and benzofuran-4-carbonyl chloride (0.066 g, 0.36mmol) as a colourless amorphous solid (0.098 g, 68%). Mass spectrum(Electrospray LC/MS): Found 478 (MH⁺). C₂₆H₂₄FN₃O₃S requires 477.

EXAMPLE 124

(S)-2(((3,4-Difuoro)phenyl)carbonylaminomethyl)-1-((4-(2-hydroxymethyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine

The title compound was prepared, using the method of Example 15, from(S)-2-(((3,4-difluoro)phenyl)carbonylaminomethyl)piperidine (0.4 g, 1.58mmol) and 5-(4-fluorophenyl)-2-(hydroxymethyl)thiazole-4-carboxylic acid(0.28 g, 1.2 mmol) as a colourless amorphous solid (0.088 g, 15%). Massspectrum (Electrospray LC/MS): Found 490 (MH⁺). C₂₄H₂₂F₃N₃O₃S requires489.

It is understood that the present invention covers all combinations ofparticular and preferred subgroups described herein above.

Determination of Orexin-1 Receptor Antagonist Activity

The orexin-1 receptor antagonist activity of the compounds of formula(I) was determined in accordance with the following experimental method.

Experimental Method

HEK293 cells expressing the human orexin-1 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37° C. in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC₅₀ values(the concentration required to produce 50% maximal response) wereestimated using 11×half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂ , 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC₅₀ values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 3.0 nMhuman orexin-A using 11×half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma)and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec)to each well to give final concentrations of 2.5 mM and 4 μM,respectively. The 96-well plates were incubated for 90 min at 37° C. in5% CO₂. The loading solution containing dye was then aspirated and cellswere washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1%gelatin (Denley Cell Wash). The volume of buffer left in each well was125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell platesgently shaken and incubated at 37° C. in 5% CO₂ for 30 min. Cell plateswere then transferred to the Fluorescent Imaging Plate Reader (FLIPR,Molecular Devices) instrument and maintained at 37° C. in humidifiedair. Prior to drug addition a single image of the cell plate was taken(signal test), to evaluate dye loading consistency. The run protocolused 60 images taken at 1 second intervals followed by a further 24images at 5 second intervals. Agonists were added (by the FLIPR) after20 sec (during continuous reading): From each well, peak fluorescencewas determined over the whole assay period and the mean of readings 1-19inclusive was subtracted from this figure. The peak increase influorescence was plotted against compound concentration and iterativelycurve fitted using a four parameter logistic fit (as described by Bowenand Jerman, TiPS, 1995, 16, 413-417) to generate a concentration effectvalue. Antagonist Kb values were calculated using the equation:

K _(b) =IC ₅₀/(1+([3/EC ₅₀])

where EC₅₀ was the potency of human orexin-A determined in the assay (innM terms) and IC₅₀ is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values inthe range 6.8-9.6 at the human cloned orexin-1 receptor.

The orexin-2 receptor antagonist activity of the compounds of formula(I) was determined in accordance with the following experimental method.

Experimental Method

CHO-DG44 cells expressing the human orexin-2 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37 C in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values(the concentration required to produce 50% maximal response) wereestimated using 11×half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC50 values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 10.0 nMhuman orexin-A using 11×half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma)and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec)to each well to give final concentrations of 2.5 mM and 4 μM,respectively. The 96-well plates were incubated for 60 min at 37 C in 5%CO₂. The loading solution containing dye was then aspirated and cellswere washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1%gelatin (Denley Cell Wash). The volume of buffer left in each well was125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell platesgently shaken and incubated at 37 C in 5% CO₂ for 30 min. Cell plateswere then transferred to the Fluorescent Imaging Plate Reader (FLIPR,Molecular Devices) instrument. Prior to drug addition a single image ofthe cell plate was taken (signal test), to evaluate dye loadingconsistency. The run protocol used 60 images taken at 1 second intervalsfollowed by a further 24 images at 5 second intervals. Agonists wereadded (by the FLIPR) after 20 sec (during continuous reading). From eachwell, peak fluorescence was determined over the whole assay period andthe mean of readings 1-19 inclusive was subtracted from this figure. Thepeak increase in fluorescence was plotted against compound concentrationand iteratively curve fitted using a four parameter logistic fit (asdescribed by Bowen and Jerman, TiPS, 1995, 16, 413417) to generate aconcentration effect value. Antagonist Kb values were calculated usingthe equation:

K _(b) =IC50/(1+([3/EC50])

where EC50 was the potency of human orexin-A determined in the assay (innM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values inthe range 6.1-9.5 at the human cloned orexin-2 receptor.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

What is claimed is:
 1. A compound of formula (I):

wherein: Y represents a group (CH₂)_(n), wherein n represents 0, 1 or 2;R¹ is phenyl, naphthyl, a mono or bicyclic heteroaryl group containingup to 3 heteroatoms selected from N, O and S; or a group NR³R⁴ whereinone of R³ and R⁴ is hydrogen or optionally substituted (C₁₋₄)alkyl andthe other is phenyl, naphthyl or a mono or bicyclic heteroaryl groupcontaining up to 3 heteroatoms selected from N, O and S, or R³ and R⁴together with the N atom to which they are attached form a 5 to7-membered cyclic amine which has an optionally fused phenyl ring; anyof which R¹ groups may be optionally substituted; R² represents phenylor a 5- or 6-membered heteroaryl group containing up to 3 heteroatomsselected from N, O and S, wherein the phenyl or heteroaryl group issubstituted by R⁵, and further optional substituents; or R² representsan optionally substituted bicyclic aromatic or bicyclic heteroaromaticgroup containing up to 3 heteroatoms selected from N, O and S; R⁵represents an optionally substituted (C₁₋₄)alkoxy, halo, optionallysubstituted (C₁₋₆)alkyl, optionally substituted phenyl, or an optionallysubstituted 5- or 6-membered heterocyclic ring containing up to 3heteroatoms selected from N, O and S; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 wherein Y is (CH₂)_(n)where n is
 1. 3. A compound according to claim 1 wherein R¹ is anoptionally substituted phenyl or benzofuranyl.
 4. A compound accordingto claim 1 wherein R² represents optionally substituted phenyl,thiazolyl, pyrazolyl, 1,2,3-triazolyl, pyridazyl, isoxazolyl orthiophenyl.
 5. A compound according to claim 1 wherein R⁵ represents anoptionally substituted phenyl, pyridyl, oxadiazolyl, furanyl,pyrimidinyl or methoxy group.
 6. A compound according to claim 1 whereinR² is optionally substituted by halogen, cyano, optionally substituted(C₁₋₆)alkyl, optionally substituted (C₁₋₆)alkoxy, or R^(a)R^(b)N—wherein R^(a) and R^(b) independently represent a hydrogen atom or a(C₁₋₄)alkyl group.
 7. A pharmaceutical composition comprising a compoundof formula (I) as defined in claim 1, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 8. A method oftreating or preventing a disease or disorder where an antagonist of ahuman orexin receptor is required, which comprises administering to asubject in need thereof an effective amount of a compound of formula (I)as defined in claim 1, or a pharmaceutically acceptable salt thereof. 9.The method according to claim 8, wherein said disease or disorder isselected from obesity, obesity associated with Type II diabetes, and asleep disorder.
 10. The method according to claim 8, wherein saiddisease or disorder is insomnia.
 11. A compound according to claim 1:(RS)-2-(benzamidomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl-piperidine;(RS)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)-2-((3-phenylureido)methyl)piperidine;(RS)-2-((2-furyl)carbonylaminomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine;(RS)-2-(2-pyridylamidomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine;(RS)-2-((3-((4-fluoro)phenyl)ureido)methyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine;(RS)-2,3-dihydroindole-1-carboxylic acid(1-(1-(2-(3-methyl-(1,2,4)-oxadiazol-5-yl)-phenyl)-methanoyl)piperidin-2-ylmethyl)amide;(S)-2-(((4-fluoro)phenyl)carbonylaminomethyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine;(S)-2-((3-((4-fluoro)phenyl)ureido)methyl)-1-((4-(2-methyl-5-phenyl)thiazolyl)carbonyl)piperidine;(S)-2-((7-benzofuranyl)carbonylaminomethyl)-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine;(S)-2-((4-benzofuranyl)carbonylaminomethyl)-1-((4-(2-methyl-5-(4-fluorophenyl))thiazolyl)carbonyl)piperidine;(S)-2-(((3,4-difluoro)phenyl)carbonylaminomethyl)-1-((4-(2-hydroxymethyl-5-(4-(fluorophenyl))thiazolyl)carbonyl)piperidine;or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1, having the formula:

wherein R² R¹

—Ph

or a pharmaceutically acceptable salt thereof.
 13. A compound accordingto claim 1, having a formula:

wherein: R² R¹

—NHPh

—NHPh

—NHPh(4-F)

—NHPh(4-F)

or a pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 1, having the formula:

wherein: R² R¹

or a pharmaceutically acceptable salt thereof.
 15. A compound accordingto claim 1, having the formula:

wherein: R² R¹

or a pharmaceutically acceptable salt thereof.
 16. A compound accordingto claim 1, having the formula:

wherein: R² R¹ *

S

R

or a pharmaceutically acceptable salt thereof.
 17. A compound accordingto claim 1, having the formula:

R² R¹ *

S

or a pharmaceutically acceptable salt thereof.
 18. A compound accordingto claim 1, having the formula:

wherein: R² R¹

or a pharmaceutically acceptable salt thereof.